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https://www.readbyqxmd.com/read/29342230/metformin-as-an-anti-cancer-agent-actions-and-mechanisms-targeting-cancer-stem-cells
#1
Nipun Saini, Xiaohe Yang
Metformin, a first line medication for type II diabetes, initially entered the spotlight as a promising anti-cancer agent due to epidemiologic reports that found reduced cancer risk and improved clinical outcomes in diabetic patients taking metformin. To uncover the anti-cancer mechanisms of metformin, preclinical studies determined that metformin impairs cellular metabolism and suppresses oncogenic signaling pathways, including receptor tyrosine kinase, PI3K/Akt, and mTOR pathways. Recently, the anti-cancer potential of metformin has gained increasing interest due to its inhibitory effects on cancer stem cells (CSCs), which are associated with tumor metastasis, drug resistance, and relapse...
October 7, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/29340030/increased-efficacy-of-metformin-corresponds-to-differential-metabolic-effects-in-the-ovarian-tumors-from-obese-versus-lean-mice
#2
Jianjun Han, Weiya Z Wysham, Yan Zhong, Hui Guo, Lu Zhang, Kim M Malloy, Hallum K Dickens, Gene Huh, Douglas Lee, Liza Makowski, Chunxiao Zhou, Victoria L Bae-Jump
Obesity is a significant risk factor for ovarian cancer (OC) and associated with worse outcomes for this disease. We assessed the anti-tumorigenic effects of metformin in human OC cell lines and a genetically engineered mouse model of high grade serous OC under obese and lean conditions. Metformin potently inhibited growth in a dose-dependent manner in all four human OC cell lines through AMPK/mTOR pathways. Treatment with metformin resulted in G1 arrest, induction of apoptosis, reduction of invasion and decreased hTERT expression...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29323154/effects-of-metformin-on-colorectal-cancer-stem-cells-depend-on-alterations-in-glutamine-metabolism
#3
Jae Hyun Kim, Kyoung Jin Lee, Yoojeong Seo, Ji-Hee Kwon, Jae Pil Yoon, Jo Yeon Kang, Hyun Jung Lee, Soo Jung Park, Sung Pil Hong, Jae Hee Cheon, Won Ho Kim, Tae Ii Kim
Metformin has been known to suppress cancer stem cells (CSCs) in some cancers. However, the differential effects of metformin on CSCs and their mechanisms have not been reported. Herein, metformin induced pAMPK activation and pS6 suppression in metformin-sensitive (HT29) cells, but not in metformin-resistant (SW620) cells. The oxygen consumption rate was higher in HT29 cells than in SW620 cells and showed a prominent decrease after metformin treatment in HT29 cells. In glutamine-depleted medium, but not in low-glucose medium, SW620 cells became sensitive to the CSC-suppressing effect of metformin...
January 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29285837/the-new-metformin-derivative-hl156a-prevents-oral-cancer-progression-by-inhibiting-the-igf-akt-mtor-pathways
#4
Thuy Giang Lam, Yun Soo Jeong, Soo-A Kim, Sang-Gun Ahn
Metformin is a biguanide widely prescribed as an antidiabetic drug for type 2 diabetes mellitus patients. The purpose of this study was to observe the effects of the new metformin derivative, HL156A, on human oral cancer cell and to investigate its possible mechanisms. It was observed that HL156A significantly decreased FaDu and YD-10B cell viability and colony formation in a dose dependent manner. HL156A also markedly reduced wound closure and migration of FaDu and YD-10B cells. We observed that HL156A decreased mitochondrial membrane potential and induced ROS levels and apoptotic cells with caspase-3 and -9 activation...
December 29, 2017: Cancer Science
https://www.readbyqxmd.com/read/29245964/phenformin-has-anti-tumorigenic-effects-in-human-ovarian-cancer-cells-and-in-an-orthotopic-mouse-model-of-serous-ovarian-cancer
#5
Amanda L Jackson, Wenchuan Sun, Joshua Kilgore, Hui Guo, Ziwei Fang, Yajie Yin, Hannah M Jones, Timothy P Gilliam, Chunxiao Zhou, Victoria L Bae-Jump
Obesity and diabetes have been associated with increased risk and worse outcomes in ovarian cancer (OC). The biguanide metformin is used in the treatment of type 2 diabetes and is also believed to have anti-tumorigenic benefits. Metformin is highly hydrophilic and requires organic cation transporters (OCTs) for entry into human cells. Phenformin, another biguanide, was taken off the market due to an increased risk of lactic acidosis over metformin. However, phenformin is not reliant on transporters for cell entry; and thus, may have increased potency as both an anti-diabetic and anti-tumorigenic agent than metformin...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228105/metformin-attenuates-susceptibility-to-inflammation-induced-preterm-birth-in-mice-with-higher-endocannabinoid-levels
#6
Xiaofei Sun, Alexandra Tavenier, Wenbo Deng, Emma Leishman, Heather B Bradshaw, Sudhansu K Dey
Premature decidual senescence is a contributing factor to preterm birth. Fatty acid amide hydrolase mutant females (Faah-/-) with higher endocannabinoid levels are also more susceptible to preterm birth upon lipopolysaccharide (LPS) challenge due to enhanced decidual senescence; this is associated with MAPK p38 activation. Previous studies have shown that mammalian target of rapamycin complex 1 (mTORC1) contributes to decidual senescence and promotes the incidence of preterm birth. In the present study, we sought to attenuate premature decidual aging in Faah-/- females by targeting mTORC1 and p38 signaling pathways...
December 5, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/29182407/metformin-is-associated-with-reduced-cell-proliferation-in-human-endometrial-cancer-by-inbibiting-pi3k-akt-mtor-signaling
#7
Yan Zhao, Hongli Sun, Minjuan Feng, Jinyan Zhao, Xiaogui Zhao, Qiuyuan Wan, Dongge Cai
Metformin recently gained traction as potential anti-endometrial cancer agent for its new applications. However, the underlying mechanisms of the anti-cancer effect of metformin in the endometrial cancer have not yet been fully elucidated. Sixty-five patients diagnosed as endometrial carcinoma were grouped into (n = 33) and non-treatment mixed (n = 32) for analysis. Thirty healthy donors were recruited as controls. We attempt to investigate the effect of metformin on Ki-67, PI3K, p-AKT, p-S6K1, and p-4EBP1 staining in human endometrial cancer by immunohistochemical staining...
November 28, 2017: Gynecological Endocrinology
https://www.readbyqxmd.com/read/29167573/metformin-transiently-inhibits-colorectal-cancer-cell-proliferation-as-a-result-of-either-ampk-activation-or-increased-ros-production
#8
Angela Mogavero, Maria Valeria Maiorana, Susanna Zanutto, Luca Varinelli, Fabio Bozzi, Antonino Belfiore, Chiara C Volpi, Annunziata Gloghini, Marco A Pierotti, Manuela Gariboldi
Metformin is a widely used and well-tolerated anti-diabetic drug that can reduce cancer risk and improve the prognosis of certain malignancies. However, the mechanism underlying its anti-cancer effect is still unclear. We studied the anti-cancer activity of metformin on colorectal cancer (CRC) by using the drug to treat HT29, HCT116 and HCT116 p53-/- CRC cells. Metformin reduced cell proliferation and migration by inducing cell cycle arrest in the G0/G1 phase. This was accompanied by a sharp decrease in the expression of c-Myc and down-regulation of IGF1R...
November 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29165314/towards-natural-mimetics-of-metformin-and-rapamycin
#9
Alexander Aliper, Leslie Jellen, Franco Cortese, Artem Artemov, Darla Karpinsky-Semper, Alexey Moskalev, Andrew G Swick, Alex Zhavoronkov
Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally-occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects...
November 15, 2017: Aging
https://www.readbyqxmd.com/read/29137418/a-randomized-phase-ii-study-of-aromatase-inhibitors-plus-metformin-in-pre-treated-postmenopausal-patients-with-hormone-receptor-positive-metastatic-breast-cancer
#10
Yannan Zhao, Chengcheng Gong, Zhonghua Wang, Jian Zhang, Leiping Wang, Sheng Zhang, Jun Cao, Zhonghua Tao, Ting Li, Biyun Wang, Xichun Hu
Background: Everolimus significantly improves progression-free survival (PFS) and has been approved to use in aromatase inhibitor pretreated patients with hormone receptor positive advanced breast cancer. Metformin has been shown to inhibit mTOR pathway, with more favorable safety profile, leading to this hypothesis-generating trial to assess whether metformin enhances the efficacy of aromatase inhibitors. Methods: 60 postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer were randomly assigned 1:1 to aromatase inhibitor (exemestane 25mg/d or letrozole 2...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29094287/targeting-ampk-mtor-and-%C3%AE-catenin-by-combined-metformin-and-aspirin-therapy-in-hcc-an-appraisal-in-egyptian-hcc-patients
#11
Doaa Ali Abdelmonsif, Ahmed S Sultan, Wessam F El-Hadidy, Dina Mohamed Abdallah
BACKGROUND: Hepatocellular carcinoma (HCC) is an expanding health problem with a great impact on morbidity and mortality, both in Egypt and worldwide. Recently, metformin and aspirin showed a potential anticancer effect on HCC, although the mechanism of this effect is not fully elucidated. OBJECTIVE: The current work aimed to investigate the possibility of targeting AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and β-catenin proteins through combined metformin/aspirin treatment in the HepG2 cell line, and to explore such molecular targets in Egyptian HCC patients...
November 1, 2017: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/29080083/evaluation-of-metformin-effects-in-the-chronic-phase-of-spontaneous-seizures-in-pilocarpine-model-of-temporal-lobe-epilepsy
#12
Soraya Mehrabi, Nima Sanadgol, Mahmood Barati, Ali Shahbazi, Gelareh Vahabzadeh, Mitra Barzroudi, Morteza Seifi, Mazaher Gholipourmalekabadi, Fereshteh Golab
Temporal lobe epilepsy (TLE) is a common form of drug-resistant epilepsy that sometimes responds to dietary manipulation such as the 'ketogenic diet'. Here we have investigated the effects of metformin in the rat pilocaroin model of TLE. Male rats were treated with intra peritoneal injection of pilocarpine hydrochloride, in dose of 360 mg/kg to induce status epilepticus (SE). At 45 day after induction of SE, metformin was injected intraperitoneally in dose of 250 mg/kg/day for 5 days. We show that metformin potently reduces the progression of seizures and blocks seizure-induced over-expression of brain-derived neurotropic factor (BDNF) and its receptor, Tropomyosin receptor kinase B (TrkB)...
October 27, 2017: Metabolic Brain Disease
https://www.readbyqxmd.com/read/28985184/sirolimus-precipitating-diabetes-mellitus-in-a-patient-with-congenital-hyperinsulinaemic-hypoglycaemia-due-to-autosomal-dominant-abcc8-mutation
#13
Antonia Dastamani, Maria Güemes, Joanna Walker, Pratik Shah, Khalid Hussain
BACKGROUND: Sirolimus (mTOR inhibitor) is proven to be effective in children with congenital hyperinsulinism (CHI). Studies in animals suggest that sirolimus may have diabetogenic actions. However, its role in precipitating diabetes mellitus (DM) in children with CHI has not been reported. CASE PRESENTATION: A 16-year-old female with CHI due to a dominant ABCC8 gene mutation was switched from diazoxide therapy to sirolimus, due to the hypertrichosis side effect of diazoxide...
October 26, 2017: Journal of Pediatric Endocrinology & Metabolism: JPEM
https://www.readbyqxmd.com/read/28964970/metformin-triggers-apoptosis-in-pel-cells-and-alters-bortezomib-induced-unfolded-protein-response-increasing-its-cytotoxicity-and-inhibiting-kshv-lytic-cycle-activation
#14
Marisa Granato, Maria Saveria Gilardini Montani, Maria Anele Romeo, Roberta Santarelli, Roberta Gonnella, Gabriella D'Orazi, Alberto Faggioni, Mara Cirone
Metformin, the most used drug for the treatment of diabetes type 2 patients, has been shown to have anti-cancer properties. In this study, we found that metformin induced apoptosis in Primary Effusion Lymphoma (PEL) cells, an aggressive B cell lymphoma associated with KSHV against which the conventional therapies usually fail. The cytotoxic effect of metformin correlated with intracellular reactive oxygen species reduction, activation of AMPK, the inhibition of pro-survival pathways such as mTOR and STAT3 and the down-regulation of v-FLIP, a latent viral antigen that also plays a pivotal role in PEL cell survival...
December 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28962892/effects-of-metformin-on-cell-growth-and-ampk-activity-in-pituitary-adenoma-cell-cultures-focusing-on-the-interaction-with-adenylyl-cyclase-activating-signals
#15
Lara Faggi, Andrea Giustina, Giovanni Tulipano
For a few years we have been investigating AMP-activated protein kinase (AMPK) as a target for drug therapy of GH-secreting pituitary adenomas. Aim of this study was to investigate the direct effects of metformin, which causes AMPK activation in different cell types, on rat pituitary adenoma cell growth and on related cell signalling pathways. Our results suggest that metformin can exert a growth-inhibitory activity in rat pituitary tumor cells mediated by AMPK activation, although multiple mechanisms are most likely involved...
September 27, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28933290/nutraceuticals-and-repurposed-drugs-of-phytochemical-origin-in-prevention-and-interception-of-chronic-degenerative-disease-and-cancer
#16
Adriana Albini, Barbara Bassani, Denisa Baci, Katiuscia Dallaglio, Matteo Gallazzi, Paola Corradino, Antonino Bruno, Douglas M Noonan
Chronic, degenerative diseases are often characterized by inflammation and aberrant angiogenesis. For many of these pathologies, including rheumatoid arthritis, cardiovascular and autoimmune diseases, cancer, diabetes, and obesity, current therapies have limited efficacy, thus the validation of novel (chemo)preventive and interceptive approaches, of new or repurposed agents, alone or in combination with registered drugs, are urgently required. Phytochemicals (triterpenoids, flavonoids, retinoids) and their derivatives, non-steroidal anti-inflammatory drugs (aspirin) as well as biguanides (metformin and phenformin) originally developed from phytochemical backbones, are multi-target agents showing anti-angiogenic and anti-anti-inflammatory proprieties...
September 20, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28922161/comorbidity-analysis-between-alzheimer-s-disease-and-type-2-diabetes-mellitus-t2dm-based-on-shared-pathways-and-the-role-of-t2dm-drugs
#17
Reagon Karki, Alpha Tom Kodamullil, Martin Hofmann-Apitius
BACKGROUND: Various studies suggest a comorbid association between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) indicating that there could be shared underlying pathophysiological mechanisms. OBJECTIVE: This study aims to systematically model relevant knowledge at the molecular level to find a mechanistic rationale explaining the existing comorbid association between AD and T2DM. METHOD: We have used a knowledge-based modeling approach to build two network models for AD and T2DM using Biological Expression Language (BEL), which is capable of capturing and representing causal and correlative relationships at both molecular and clinical levels from various knowledge resources...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28919040/heme-binding-biguanides-target-cytochrome-p450-dependent-cancer-cell-mitochondria
#18
Zhijun Guo, Irina F Sevrioukova, Ilia G Denisov, Xia Zhang, Ting-Lan Chiu, Dafydd G Thomas, Eric A Hanse, Rebecca A D Cuellar, Yelena V Grinkova, Vanessa Wankhede Langenfeld, Daniel S Swedien, Justin D Stamschror, Juan Alvarez, Fernando Luna, Adela Galván, Young Kyung Bae, Julia D Wulfkuhle, Rosa I Gallagher, Emanuel F Petricoin, Beverly Norris, Craig M Flory, Robert J Schumacher, M Gerard O'Sullivan, Qing Cao, Haitao Chu, John D Lipscomb, William M Atkins, Kalpna Gupta, Ameeta Kelekar, Ian A Blair, Jorge H Capdevila, John R Falck, Stephen G Sligar, Thomas L Poulos, Gunda I Georg, Elizabeth Ambrose, David A Potter
The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs...
October 19, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28915708/targeting-metabolism-and-amp-activated-kinase-with-metformin-to-sensitize-non-small-cell-lung-cancer-nsclc-to-cytotoxic-therapy-translational-biology-and-rationale-for-current-clinical-trials
#19
REVIEW
Michael Troncone, Stephanie M Cargnelli, Linda A Villani, Naghmeh Isfahanian, Lindsay A Broadfield, Laura Zychla, Jim Wright, Gregory Pond, Gregory R Steinberg, Theodoros Tsakiridis
Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28833603/metformin-incombination-with-curcumin-inhibits-the-growth-metastasis-and-angiogenesis-of-hepatocellular-carcinoma-in-vitro-and-in-vivo
#20
Hui-Hui Zhang, Ying Zhang, Yan-Na Cheng, Fu-Lian Gong, Zhan-Qi Cao, Lu-Gang Yu, Xiu-Li Guo
Hepatocellular carcinoma (HCC) has poor prognosis due to the advanced disease stages by the time it is diagnosed, high recurrence rates and metastasis. In the present study, we investigated the effects of metformin (a safe anti-diabetic drug) and curcumin (a turmeric polyphenol extracted from rhizome of Curcuma longa Linn.) on proliferation, apoptosis, invasion, metastasis and angiogenesis of HCC in vitro and in vivo. It was found that co-treatment of metformin and curcumin could not only induce tumor cells into apoptosis through activating the mitochondria pathways, but also suppress the invasion, metastasis of HCC cells and angiogenesis of HUVECs...
August 19, 2017: Molecular Carcinogenesis
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